Jie Bai and Qi Zheng

Jie Bai is with Graduate School Office,Xi'an Medical University,Xi'an,China

Abstract—Morphine belongs to opioid analgesics,which acts on the central nervous system.It can improve emotional responses such as anxiety,tension,and fear caused by pain and relieve it.Morphine had been widely used in the treatment of cancer-related pain.However,a series of opioidassociated adverse effects including opioid-induced respiratory depression were reported in clinical practice.Here,we reported a unique patient diagnosed with lung cancer,who underwent respiratory depression resulting from oral administration of ten milligram of morphine and was successfully resuscitated by naloxone.A literature review is then performed to analyze this rare condition.

Key words—Morphine,Respiratory depression,Naloxone

INTRODUCTION

As a general rule,opioid-associated adverse effects(such as constipation,nausea and vomiting,pruritus,delirium,respiratory depression,etc.)should not be neglected easily,especially if multiple agents are used.Significantly,opioid-induced respiratory depression(OIRD)is one of the most severe side effects[1].In general,high initial titration dose of opioids is the main cause of respiratory depression.And respiratory depression is characterized by mild and irregular respiratory changes,which can lead to hypercapnia,insufficient oxygen supply and even death[2].However,our patient developed dyspnea with heavily sweating after taking only ten milligram(mg)of morphine orally.Although there were no clinical manifestations of hypersomnia and miosis,the patient’s recent medication history was reviewed and there were no other abnormalities.OIRD was highly suspected.Naloxone was infused immediately,and the above symptoms were completely relieved after 5 minutes.According to Naranjo adverse drug reactions assessment scale,the patient received a score of 5,which means"possible adverse reaction"[3].This case report described a rare serious adverse event caused by low-dose morphine.A therapeutic dose of morphine can cause respiratory depression,which should be paid high attention by doctors.

CASE PRESENTATION

A 52-year-old woman was admitted in our hospital for intermittent pain in her left shoulder lasting over one month.The patient had been diagnosed as left lung adenocarcinoma with left pleural effusion,multiple bone metastases and left thoracic wall metastases.In the past eight months,she had undergone five cycles of chemotherapy and one cycle of radiotherapy on thoracic wall metastases.According to the patient’s descriptions,the pain in the left shoulder was significant and did not radiate to other parts of the body.The numerical rate sore(NRS)of pain was six to seven(moderate to severe pain).Before being admitted,5 mg of oxycodone and acetaninophen tablet(OA,5 mg per tablet)every 6 hours had been used to abate her pain.Though effective,this dose of OA was associated with significant dizziness and was therefore abandoned.The standard body and laboratory examinations showed no abnormal signs except for anemia.The blood test showed HGB 48 g/L,ALP 322 U/L,GGT 114 U/L and ALB 34 g/L.The X-ray scan showed bone metastases of the fourth and fifth cervical vertebrae,which conformed to the pain areas.Then a series of therapeutic measures were taken,including blood transfusion,zoledronic acid use,supportive treatment and palliative radiotherapy.OA was replaced with 10 mg of oral morphine tablet every 4 hours to control her pain.Initially,the patient exhibited mild nausea and vomiting after 10 minutes of oral use,with complete pain relief.Fifty minutes later,however,dyspnea unexpectedly occurred and aggravated greatly.The patient breathed deeply and difficultly,with heavily sweating.Lungs physical examination:left tactile vocal fremitus was weakened,percussion of inferior lobe of left lung was flatness,the breathing sound of the left lung was weakened by auscultation,and the breathing sound of the right lung was clear.The wheezes,crackles and pleural friction rub were not heard on bilateral pulmonary,which was consistent with the signs of cancer of the inferior lobe of left lung and pleural effusion,and there was no significant difference from hospital admission.At the same time,the diameter of pupils was normal.In addition,patient had low hemoglobin,combined with the patient's allergic physique,we used dexamethasone prophylactically for allergies before the patient received blood transfusions,no allergic reaction was found in the patient before morphine analgesia(using OA analgesia),and there was no overlap between morphine and blood transfusion.Reviewing patient’s recent medication history had no obvious abnormalities,so respiratory depression caused by drugs and blood transfusion was basically ruled out.For all these reasons,morphine-induced respiratory depression was highly suspected.therefore 0.4 mg of naloxone(dilute one ampule of naloxone(1 mL)into 9 mL of saline for a total volume of 10 mL,give 1-2 mL every 30-60 seconds),the specific antagonist of morphine was infused at once.Fortunately,those symptoms were fully relieved within 5 minutes,without any lingering effects.In the end,the patient had to select other analgesic drugs to control her cancer pain.

DISCUSSION

Pain is one of the most common complications in advanced cancers,with the prevalence over 70%[4,5].Strong opioids play a vital role in treating moderate to severe cancer-related pain and morphine is the most widely used agent.Although a lot of strong opioids(such as hydromorphone,oral methadone,oxycodone,transdermal fentanyl,etc.)are available and prescribed,there is no superiority of one over another[6].Until now,oral morphine is regarded as the first choice for moderate to severe cancer pain.According to a systematic review including 62 studies,use of oral morphine was considered as an effective analgesic for cancer pain,with a low rate(6%)of intolerable adverse events[7].In fact,opioids usually take effects rapidly via being titrated by immediate and slow-release oral morphine formulations.The aim of titration is to modified the opioid dose speedily to achieve full relief of pain without unacceptable adverse effects.Individual titrations of opioid should usually start at the minimum recommended dose and increase until optimum analgesia without unacceptable side effects attain[8].In this case,the patient was suggested to take the minimum dose of oral morphine(10 mg)as the initial titration,which conformed to the standard schedule of titration.Out of our expectation,an acute and severe respiratory depression happened,which is very infrequently seen in clinical practice.

The most significant effect of opioids on breathing is to change the rhythm and pattern of breathing,mainly by stimulating the mu opioid receptors(MORs)in the medulla oblongata preBötzinger complex and the pons Kölliker-Fuse nucleus to produce respiratory depression.Opioid receptor agonists can reduce respiratory rate by acting on the preBötzinger complex[9],and the Kölliker-Fuse nucleus plays an important role in maintaining respiratory rate,tidal volume,transition between inspiratory and expiratory phases,and opening of the upper respiratory tract[10].Therefore,OIRD is a combination of decreased respiratory drive,decreased level of consciousness,and upper airway obstruction,which ultimately leads to reduced alveolar ventilation and increased arterial carbon dioxide levels[2].Experts agree that patients with limited cardiopulmonary reserve are more susceptible and hypercarbia occurs before hypoxia[11].In addition,liver dysfunction reduces the overall clearance rate of opioids.After oral administration,the liver’s metabolic capacity decreases,the first pass elimination effect decreases,and the bioavailability increases.The above two factors led to the increase in the blood concentration of opioid drugs,and the increase in the incidence of toxic and side effects caused by drug accumulation[12].In another study,patients with cardiac,respiratory disease and/or obstructive sleep apnoea were at relatively higher risk for postoperative OIRD after surgery[13].As for our patient,the liver function was slightly abnormal,it was not enough to affect the metabolism of morphine.And the lung cancer and pleural effusion did not seem to influence her performance status,but the anemia(48 g/L)is liable to result in hypoxemia,which might be a risk factor of OIRD.On the other hand,the patient had a history of hypersensitivity to a good many drugs.When using the opioid OA the patient showed significant dizziness which imply her increased risk of OIRD.

Naloxone,a short-acting opioid antagonist,remains an effective antidote for the rescue of severe opioid-induced complications[6].Therefore,naloxone is demanded to be available in medical institutions to prevent patients taking opioids from high risk of respiratory depression and sedation.In our case,the OIRD was rapidly relieved thanks to timely infusion of naloxone.However,naloxone is also associated with side effects including pulmonary edema,cardiac arrhythmias,and cardiac arrest[11].In the future,needle-free naloxone preparations or other opioid antagonist with high efficiency and low toxicity may be developed to improve the use of naloxone[14].In recent years,drugs that selectively reverse OIRD have attracted more and more attention.These drugs work through nonopioid receptor systems.Without affecting the analgesic effect,they can not only restore breathing to an acceptable level,but can even prevent OIRD[15].

The reason for sharing this case is when patients are treated with morphine analgesia,even if there is no classic OIRD manifestations of hypersomnia and miosis,and respiratory depression cannot be explained by the condition,then OIRD should be highly suspected.The respiratory depression was reversed after Naloxone treatment,and the Naranjo adverse drug reactions assessment scale also further confirmed our conjecture.In conclusion,morphine still plays an important role in the treatment of cancerrelated pain,but its side effects,such as morphine-induced respiratory depression,should not be easily neglected.Early detection and timely treatment are the key to the treatment of OIRD.

ACKNOWLEDGMENT

The authors did not receive any funding for this study.

Competing interests:The authors declare that they have no conflict of interest.

Citation:Bai J,Zheng Q.Acute respiratory depression resulting from ten milligram of oral morphine:an unusual case.TMR Cancer.2021;4(3):12.doi:10.53388/TMRC20 1800104.

Executive editor:Xiao-Hong Sheng.

Submitted:18 March 2021,Accepted:28 April 2021,

Online:28 June 2021

© 2021 By Authors.Published by TMR Publishing Group Limited.This is an open access article under the CC-BY license(http://creativecommons.org/licenses/BY/4.0/)